Figure 4 - Mutationally activated K-Ras suppresses differentiation in Apc-mutant colon cancers.

(a) Hematoxylin and eosin staining of a polyp expressing wild-type K-Ras and N-Ras. This lesion is a composed largely of well-differentiated epithelium. (b) High-magnification view of a tumor expressing wild-type K-Ras and N-Ras, showing a well-differentiated region with a terminally differentiated goblet cell (arrow). (c) Hematoxylin and eosin staining of a polyp expressing activated K-Ras. The tumor epithelium is highly dysplastic. (d) High-magnification view of a tumor expressing K-Ras^G12D. Note the stratified epithelium, serrated crypt borders, high nucleus to cytoplasm ratio and lack of terminally differentiated goblet cells. (e) Hematoxylin and eosin staining of a tumor expressing activated N-Ras, which is histologically similar to a tumor expressing wild-type K-Ras and N-Ras. (f) High-magnification view of a tumor expressing activated N-Ras showing benign epithelium. (g) Immunohistochemistry for Mcm6 on a tumor expressing wild-type K-Ras and N-Ras. Small, focal areas are positive for Mcm6 (red cells, white arrow), but the poorly differentiated region of the tumor (outlined in white) is largely negative for this marker. (h) Immunohistochemistry for Msi1 on a tumor expressing wild-type K-Ras and N-Ras, showing focal expression (arrow) within the poorly differentiated region of the tumor (outlined in black). (i) Immunohistochemistry for -catenin (Ctnnb1) on a tumor expressing wild-type K-Ras and N-Ras, showing widespread expression throughout the poorly differentiated region of the tumor. (j) Immunohistochemistry for Mcm6 on a tumor expressing K-Ras^G12D, showing expression throughout the tumor epithelium. (k) Immunohistochemistry for Msi1 on a tumor expressing mutant K-Ras. As with Mcm6, the entire tumor epithelium is positive for this stem cell marker. (l) Immunohistochemistry for -catenin on a tumor expressing activated K-Ras, showing widespread expression throughout the tumor. Scale bar in all panels, 50 m. All histology is from animals at 3 months of age. Mcm6, antibody to Mcm6. Msi1, antibody to Msi1; Ctnnb1, antibody to -catenin.